Novel basic derivatives of benz[e] isoindol-1-ones and pyrrolo[3,4-c] quinolin-1ones with 5-HT3-antagonistic activity, their preparation and their therapeutic use

ABSTRACT

Novel basic derivatives of benz[e]isoindol-1-ones and pyrrolo[3,4-c]quinolin-1-ones which can be represented by the general formula (I) indicated below are described:  
                 
 
     in which  
     X is CH or N,  
     R is H, Cl or OR 1  in which R 1  is H or an alkyl group having from 1 to 3 carbon atoms,  
     Het is the 3-endotropyl group (that is, the 8-methyl-8-azadicyclo[3.2.1]oct-3-yl group) or the 3-quinuclidyl group (that is, the 1-azadicyclo[2.2.2]oct-3-yl group); these compounds have been found to be potent and selective antagonists of the 5-HT 3  serotonin-like receptor and can therefore be used, for example, as anti-emetics as well as in various pathological conditions of the central nervous system, and as antitussives.

DESCRIPTION

[0001] The subject of the present invention novel basic derivatives ofbenz[e]isoindol-1-ones and pyrrolo[3,4-c]quinolin-1-ones which can berepresented by the general formula (I) indicated below:

[0002] and in which

[0003] X is CH or N,

[0004] R is H, Cl or OR₁ in which R₁ is H or an alkyl group having

[0005] from 1 to 3 carbon atoms,

[0006] Het is the 3-endotropyl group (that is, the8-methyl-8-azadicyclo[3.2.1]oct-3-yl group) or the 3-quinuclidyl group(that is, the 1-azadicyclo[2.2.2]oct-3-yl group).

[0007] The compounds of the present invention have been found to bepotent and selective antagonists of the 5-HT₃ serotoninergic receptorand can therefore advantageously be used in the treatment of variousdiseases in man, for example, as anti-emetics, particularly for vomitingassociated with antitumoral chemotherapy, and in various pathologicalconditions of the central nervous system such as, for example, anxiety,depression, schizophrenia, psychosis, Alzheimer's disease and seniledementia, and also as antitussives. Since serotonin is also known to beinvolved in the regulation of the peristalsis of the gastrointestinaltract, the compounds of the invention can also advantageously be used asprokinetic agents in various pathological conditions connected withhypomotility of the gastrointestinal tract such as, for example,non-ulcerous dyspepsia, reflux oesophagitis and in irritable bowelsyndrome.

[0008] In addition to the compounds currently used in treatment asanti-emetics, such as Granisetron and Ondasetron, many publications andpatents describe novel compounds with 5-HT³ antagonistic activity. Thus,for example, U.S. Pat. No. 5200413 describesN-azadicyclo-indol-1-carboxyamides with 5-HT-antagonistic activity; U.S.Pat. No. 5,260,303 describes azacyclo-imidazopyridines with5-HT₃-antagonistic activity, U.S. Pat. No. 5,280,028 describesbenzimidazole derivatives active as 5-HT₃-antagonists and5-HT₄-antagonists, U.S. Pat. No. 5,399,562 describes indolonederivatives substituted with groups such as endotropyl and quinuclidylgroups. Recently, tropyl-azaindole derivatives with mixed 5-HT₃- andsigma-oppioid-antagonist activity having antitussive activity (WO04742-A-1995), 1-heteroaryl-4-alkyl-4-aminopiperidine derivatives whicheasily overcome the blood-brain barrier [EP-647639-A (1995)],tetrahydrobenzimidazole derivatives with mixed anti-5-HT₃ and H₃histamine activity [WO 9509168-A(1995)] and imidazol-4-yl-piperidinederivatives with mixed anti-5-HT₃ and -5-HT₄ activity(EP-646583-A(1995)] have also been described. All of this research showsthat there is a great therapeutic need to find novel, ever more potent,selective and better tolerated drugs with 5-E₃-antagonistic activity. Inaccordance with this need, the object of the present invention is toprovide novel drug treatments having potent and selective5-HT₃-antagonistic activity for the treatment of all pathologicalconditions, both central and peripheral, which are due to poor operationof the 5-HT₃ serotoninergic receptor system. Pharmaceutical forms of thecompounds of the invention can be prepared by conventional techniques,for example, as tablets, capsules, suspensions, solutions, suppositoriesor patches, and may be administered orally, parenterally, rectally ortransdermally, or as other forms suitable for achieving the therapeuticeffect such as, for example, solid preparations for oral use withprotracted action which permit controlled release of the activesubstance over time.

[0009] The active ingredient is normally administered to the patientwith a reference dose variable from 0.001 to 1 mg/kg of body weight perdose. For parenteral administration, the use of a water-soluble salt ofthe compounds of the invention, such as the hydrochloride or anothernon-toxic and pharmaceutically acceptable salt, is preferable. Asinactive ingredients, substances commonly used in pharmaceuticaltechnology such as excipients, binders, flavorings, disaggregants,colorings, humectants, etc. may be used.

[0010] The method of preparing the derivatives of the invention consistsof a series of reactions which comprise:

[0011] a) reacting esters of formula (IV)

[0012] prepared as described by Mayer et al (Berichte 1922, 55,1835-1861), in which X and R have the meanings given above and R′ may bemethyl or ethyl, with N-bromosuccinimide in the presence of benzoylperoxide, in an organic solvent such as, for example, carbontetrachloride, at a temperature between ambient temperature and thereflux temperature of the solvent, for a period of between 1 and 8 h, togive the corresponding 2-bromomethyl derivatives of formula III (seeSynthesis scheme 1, step 1);

[0013] b) reacting the bromo derivatives of formula III

[0014] with a stoichiometric quantity of a heterocyclic amine of formula(II)

NH₂-Het  (II)

[0015] in which Het is the 3-endotropyl group, that is, the8-methyl-8-azadicyclo[3.2.1.]oct-3-yl group, in the presence of an inerttertiary base which functions as a proton acceptor, or with an excess ofthe amine (II), at the reflux temperature of an anhydrous solvent,preferably toluene, nor a period of between 1 and 24 h, to give thecorresponding amide derivatives of forms a (I) in accordance withSynthesis scheme 1, step 2. The compounds of formula (I) in which R isOH are prepared by hot acid hydrolysis of the corresponding etherealdervazives.

[0016] Synthesis scheme 1

[0017] Step 1

[0018] The method for the preparation of the derivatives of theinvention in which Het is the 3-quinuclidyl group (that is, the1-azadicyclo[2.2.2]oct-3-yl group) consists of a series of reactionsillustrated by Synthesis scheme 2, comprising: protecting the tertiaryendocyclic nitrogen of the 3-aminoquinuclidine by alkylation with allybromide, reacting the non-isolated Quaternizea intermediate (VI) withthe appropriate bromine derivative of formula (III) indicated in Scheme1, to give the quaternary ammoniacal salt of the cyclized compound (V)which, in turn, is not isolated, and deprotecting hot withn—dipropylamine in dimethyl formamide in the presence of a catalyticquantity of Pd(PPh₃)₂Cl₂ to give amide derivatives of formula (I)according to Synthesis scheme 2, step 3, in which Het is the3-quinuclidyl group and X and R have the meanings given above.

[0019] in which Het is the 3-quinuclidyl group (that is, the 1-azadicyclo[2.2.2.]oct-3-yl group).

[0020] The following examples are given below to illustrate theinvention further.

EXAMPLE 1endo-2-[8-methyl-8-azadicyclo[3.2.1.]oct-3-yl-2,3-dihydro-1H-benz[e]isoindol-1-one(Compound 1 of Table 1)

[0021] A mixture constituted by 10 g (51 mmoles) of2-methyl-1-naphthalene methyl carboxylate, 9.9 g (55.6 mmoles) ofN—bromosuccinimide, and 1.5 g (6.2 mmoles) of benzoyl peroxide in 300 mlof CCl₄ was heated under reflux for 2 h. The solvent was evaporated, theresidue was taken up with the minimum quantity of CCl₄, the succinimidewas filtered out, and the filtrate was evaporated under reduced pressureto give 15 g of yellowish oil which was used as such for the subsequentreaction (NMR indicated that this oil was constituted by 85-95% of2-bromomethyl-1-naphthalene methyl carboxylate). A mixture of 15 g ofthis oil with 25.9 g (185 mmoles) of endo-3-aminotropane in 500 ml oftoluene was heated under reflux for 8 h with azeotropic removal of themethanol evolved in the course of the reaction. The solvent wasevaporated under reduced pressure, the residue was taken up with CHCl₃,washed with water and then with a saturated NaCl solution, dehydratedand evaporated under reduced pressure. The oily residue, treated withhexane-ethyl acetate, was rendered friable by resting. It wasrecrystallized from ethyl acetate, to give 8.5 g. Yield 54.5%. Meltingpoint 174-175° C. H NMR (CDCl₃): 1.54-1.61 (m, 4H), 2.15-2.19 (m, 2H),2.25-2.60 (m, 5H), 3,28 (m, 2H), 4.41 (s, 2H), 4.64 (m, 1H), 7.47-7.67(m, 3H), 7.90 (d, J=7.6, 1H), 7.97 (d, J=8.3, 1H), 9.24 (d, J=8.4, 1H).

EXAMPLE 2 endo-2-[8-methyl-8-azadicyclo[3.2.1]oct-3-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (Compound 2 of Table 1)

[0022] The method described in Example 1 was followed with the use of3-methyl-4-quinoline ethyl carboxylate instead of the 2-methyl-1-naphthalene methyl carboxylate. After reaction withN-bromosuccinimide and in the presence of benzoyl peroxide, thecorresponding 3-bromomethyl-4-quinoline ethyl carboxylate, a denseyellow-orange oil, was obtained and was reacted with an excess ofendo-3-aminotropane in toluene under reflux for 8 h. Upon completion theoily residue obtained was rendered friable and crystallized from ann-hexane-ethyl acetate mixture. Overall yield 38%. Melting point153-154° C. ¹H NMR (CDCl₃):1.50-1.65 (m, 4H), 2.14-2.21 (m, 5H),2.42-2.59 (m, 2H), 3,28 (m, 2H), 4.46 (s, 2H), 4.61 (m, 1H), 7.61-7.79(m, 2H), 8.15 (d, J=8.4, 1H), 9.05 (m, 2H), MS: m/z 307 (M⁺, 22).

EXAMPLE 3endo-2-[8-methyl-8-azadicyclo[3.2.1]oct-3-yl]-2,3-dihydro-4-chloro-1H-pyrrolo[3,4-c]quinolin-1-(Compound3 of Table 1)

[0023] This compound was synthesized by following the method used forthe synthesis of Compound 1, with the use of 8.7 g (35 mmoles) of2-chloro-3-methyl-4-quinoline ethyl carboxylate instead of the2-methyl-1-naphthalene methyl carboxylate and in accordance with thestoichiometry described above. 7.2 g of Compound 3 was obtained (yield60%). Recrystallization from n-hexane-ethyl acetate gave a pure productwhich melted at 169-171° C. ¹H NMR (CDCl₃) : 1.47-1.66 (m, 4H) ,2.16-2.23 (m, 5H), 2.45-2.60 (m, 2H), 3.29 (m, 2H), 4.41 (s, 2H), 4.67(m, 1H), 7.64-7.83 (m, 2H), 8.09 (d, J=8.3, 1H), 9.04 (d, J=8.6, 1H) ,MS: m/z 341 (M⁺, 16).

EXAMPLE 4endo-2-[8-methyl-8-azadicyclo[3.2.1]oct-3-yl]-2,3-dihydro-4-propoxy-1H-pyrrolo[3,4-c]quinolin-1-one(Compound 4 of Table 1)

[0024] This compound was synthesized by following the method used forthe synthesis of Compound 1, with the use of 2.6 g (9.5 mmoles) of2-propoxy-3-methyl-4-quinoline ethyl carboxylate instead of the2-methyl-2-naphthalene methyl carboxylate and in accordance with thestoichiometry described above. 1.5 g of Compound 4 was obtained (yield43%). After crystallization from n-hexane-ethyl acetate, a pure compoundin the form of colorless needles which melted at 170-171° C. wasobtained. ¹H NMR (CDCl₃):1.08 (t, J=7.4, 3H), 1.48-1.67 (m, 4H),1.80-1.98 (m, 2H), 2.19-2.23 (m, 5H), 2.43-2,58 (m, 2H), 3.28 (m, 2H),4.33 (s, 2H), 4.50-4.73 (m, 3H), 7.48 (t, J=7.4, 1H), 7.65 (t, J=8.1,1H), 7.90 (d, J=8.3, 1H) , 8.93 (d, J=9.0, 1H).

EXAMPLE 5endo-2-[8-methyl-8-azadicyclo[3.2.1]oct-3-yl]-2,3-dihydro-4-hydroxy-1H-pyrrolo[3,4-c]quinolin-1-one(Compound 5 of Table 1)

[0025] 8 g (24.9 mmoles) of Compound 3 was dissolved in 1 liter of 1 HCland heated to 80° C for 4 h with stirring. The reaction mixture was thencooled to 0° C., brought to pH 9 with 5N NaOH and extracted withchloroform. The organic extracts were dehydrated with anhydrous sodiumsulphate, filtered and evaporated at reduced pressure to give 7 g ofCompound 5 (yield 88%). Crystallization from ethyl acetate, gave a purecompound which melted at 245-246° C. ¹H NMR (CDCl₃): 1.46-1.61 (m, 4H),2.16-2.23 (m, 5H), 2.43-2.58 (m, 2H), 3.27 (m, 2H), 4.35 (s, 2H), 4.61(m, 1H), 7.28-7.36 (m, 2H), 7.55 (m, 1H), 8.84 (d, j=8.2, 1H), 10.63 (brs, 1H), MS: m/z 323 (M+, 28).

EXAMPLE 6(R,S)-2-[1-azadicyclo[2.2.2]oct-3-yl]-2,3-dihydro-1H-benz[e]isoindol-1-one(Compound 6 of Table 1)

[0026] A suspension of 11.2 g (56 mmoles) of 3-aminoquinuclidinedihydrochloride, 22 g (207 mmoles) of anhydrous Na₂CO₃, and 300 ml ofethanol was heated under reflux in an inert atmosphere with vigorousstirring for 1 h and was then cooled to ambient temperature andsupplemented with 4.8 ml (55 mmoles) of allyl bromide. The mixture wasallowed to react with stirring at ambient temperature for 20 min. andthen heated under reflux for 1 h and finally supplemented with 14.6 g(50 mmoles) of 2-bromomethyl-1-naphthalene methyl carboxylate (preparedas described in the synthesis method of Example 1) dissolved in theminimum quantity of ethanol. The resulting mixture was heated underreflux for 12 h. The solvent was evaporated under reduced pressure andthe residue was taken up with 500 ml of dimethyl formamide. The solidwhich had not dissolved was filtered out and the filtrate wassupplemented with 40 ml (292 mmoles) of dipropylamine and 0.5 g (0.71mmoles) of Pd(PPh₃)₂Cl₂. The resulting mixture was heated to 100° C. forabout 30 minutes in an inert nitrogen atmosphere and then poured intowater and ice and extracted with CHCl₂. The extracts were washedthoroughly with water, dehydrated over sodium sulphate and evaporated atreduced pressure. The semi-solid residue which was obtained wassolidified as a result of repeated washings with ethyl ether. 5.1 g ofpure, solid, microcrystalline Compound 6 was thus obtained. Yield 34%.Melting point 138-141° C. ¹H NMR (CDCl₃): 1.59-1.96 (m, 4H), 2.20 (m,1H), 2.89-3.18 (m, 5H), 3.41 (m,1H), 4.48 (t, J=8.3, 1H), 4.64 (m, 2H),7.49-7.68 (m, 3H), 7.90 (d, J=8.1, 1H) , 7.98 (d, J=8.4, 1H), 9.20 (d,J=8.3, 1H)

EXAMPLE 7(S)-2-[1-azadicyclo[2.2.2]oct-3-yl]-2,3-dihydro-1H-benz[e]isoindol-1-one(Compound 7 of Table 1)

[0027] The (S) enantiomer of Compound 6 was prepared by following themethod described above for Compound 6, with the use of

[0028] (S)-3-aminoquinuclidine dihydrochloride instead of(R,S)-3-aminoquinuclidine dihydrochloride. Yield 32%. Melting point152-154° C.

EXAMPLE 8(R)-2-[1-azadicyclo[2.2.2]oct-3-yl]-2,3-dihydro-1H-benz[e]isoindol-1-one(Compound 8 of Table 1)

[0029] The (R) enantiomer of Compound 6 was prepared by following themethod described above for Compound 6, with the use of(R)-3-aminoquinuclidine dihydrochloride instead of (R,S)-3-aminoquinuclidine dihydrochloride. Yield 35%. Melting point 155-157° C.

EXAMPLE 9(R,S)-2-[1-azadicyclo[2.2.2]oct-3-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one(Compound 9 of Table 1)

[0030] The method described for the preparation of Compound 6 wasfollowed, with the use of 3-bromomethyl-4-quinoline ethyl carboxylateinstead of 2-bromomethyl-1-naphthalene methyl carboxylate. Uponcompletion, the oily residue obtained was rendered friable with n-hexaneto give an amorphous solid without a definite melting point. Calculatedanalysis for C₁₈H₁₉N₃O:C, 73.69; H, 6.53; N, 14.32. Found: C, 73.98, H,6.66, N. 13.99.

[0031] Some derivatives of formula (I) produced in accordance with theinvention are given in Table 1 below with some identifying chemical andphysical characteristics, without thereby in any way limiting the spiritand subject of the invention. TABLE 1 Compounds of formula (I)

Compounds X Het R Formula Melting point Crystallization solvents 1 CH3-endo-tropyl⁽¹⁾ H C₂₀H₂₂N₂O 174-175° C. ethyl acetate 2 N 3-endo-tropylH C₁₉H₂₁N₃O 153-154° C. n-hexane-ethyl acetate 3 N 3-endo-tropyl ClC₁₉H₂₀ClN₃O 169-171° C. n-hexane-ethyl acetate 4 N 3-endo-tropyl OC₃H₇C₂₂H₂₇N₃O₂ 170-171° C. n-hexane-ethyl acetate 5 N 3-endo-tropyl OHC₁₉H₂₁N₃O₂ 245-246° C. ethyl acetate 6(R, S) CH 3-quinuclidyl⁽²⁾ HC₁₉H₂₀N₂O 153-154° C. n-hexane-ethyl ether 7(S) CH 3-quinuclidyl HC₁₉H₂₀N₂O 152-154° C. n-hexane-ethyl ether 8(R) CH 3-quinuclidyl HC₁₉H₂₀N₂O 155-157° C. n-hexane-ethyl ether 9 N 3-quinuclidyl H C₁₈H₁₉N₃Oamorphous —

DESCRIPTION OF PHARMACOLOGICAL ACTIVITY

[0032] In order to evaluate the affinity of the compounds of theinvention for the various subtypes of serotoninergic receptors,[3H]-BRL43694 (Granisetron) was used as a marked ligand for theinvestigation of the 5-HT₃ receptors, [3H]- paroxetine was used for theinvestigation of the serotonin uptake site, [3H]-ketanserine was usedfor the investigation of the 5-HT₂ receptors and [3H]-8-OH DPAT was usedfor the investigation of the 5HT-1A receptors.

[0033] a) Affinity for the 5-HT₃ receptors

[0034] The method of Nelson et al. (Biochem. Pharmacol. 1989, 38,1693-95) was followed with slight modifications. Rat cortex andhippocampus were used to produce a pellet having a final concentrationof 20 mg of tissue/sample. Specific activity of the tracer: 81 Ci/mmole;incubation time: 30 min; incubation temperature: 25° C. Specificbinding: 70% of the total; Kd=0.6×10⁻⁹M.

[0035] b) Affinity for the serotonin uptake site

[0036] The method of Plenge et al (Eur. J. Pharmacol., 1990, 189,129-134) was followed with slight modifications. The entire rat brainwas used to produce a pellet having a final concentration of 2 mg oftissue/sample. Specific activity of the tracer: 29.7 Ci/mmole;incubation time: 60 min.; incubation temperature: 25° C. Specificbinding: 75% of the total; Kd=0.09×10⁻⁹M.

[0037] c) Affinity for the 5-HT₂ receptors

[0038] The method of Leysen et al (Mol. Pharmacol. 1982, 21, 301-314)was followed with slight modifications. Rat prefrontal cortex was usedto produce a pellet having a final concentration of 8 mg oftisssue/sample. Specific activity of the tracer: 80.9 Ci/mmole;incubation time: 20 min; incubation temperature: 37° C. Specificbinding: 90% of the total; Kd=0.5×10⁻⁹M.

[0039] d) Affinity for the 5-HT_(1A) receptors

[0040] The method of Hall et al (J. Neurochem. 1985, 44, 1685-1696) wasfollowed with slight modifications. Rat hippocampus was used to producea pellet having a final concentration of 4 mg of tissue/sample. Specificactivity of the tracer: 137 Ci/mmole; incubation time 10 min; incubationtemperature: 37° C. Specific binding: 80% of the total; Kd=2.3×10⁻⁹M.

[0041] It can be seen from the data given in Table 2 that many of thecompounds of the invention are potent antagonists of the 5-HT₃ subtypereceptor. For example Compound 7 has a sub-nanomolar affinity for the5-HT₃ receptor and was the most active of all of the compounds tested.The compounds of the invention were also shown to possess a highselectivity for this receptor since they were very slightly active orinactive at the other receptor subtypes tested. It is also interestingto note that even small structural variations of the compounds of theinvention cause a significant loss of affinity for the 5HT₃ receptor.Thus, for example, Compound 10, that is, the analogous 3-hexotropylderivative of the corresponding 3-endotrophyl (Compound 1), describedherein purely for comparative purposes, was almost 2 orders oflogarithmic magnitude less active than Compound 1; similarly, Compound11 which is also given for comparative purposes, that isendo-2-[-methyl-8-azadicyclo[3.2.1]oct-3-yl]-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one,which has a “linear” polycyclic fusion and which is the pyrrolo-quinolneanalogue of compound 2 was approximately 60 times less active than thelatter, in which the polycyclic fusion takes place on the “e” face andis hence angular.

Activity in vivo

[0042] The potent 5-HT₃-antagonistic activity performed by the compoundsof the invention in vitro was confirmed in vivo in the rat in thebradycardial reflex test according to Bezold-Jarisch (Paintal, Physio.Rev. 1973, 53, 159). Serotonin injected i.v. induced a bradycardialeffect in the rat. Products 1-9 of the invention, injected in doses of0.1 mg/kg i.v. 5 minutes before the administration i.v. of 0.03 mg/kg ofserotonin completely blocked the bradycardial effect induced thereby. Itshould be noted that the same compounds injected alone, even in doses 10times higher, did not induce any variation in cardiac frequency in therat, thus behaving as pure antagonists. TABLE 2 Affinity of somecompounds of the invention for binding to various serotonin receptorsubtypes (Ki(nM) ± SE) 5-HT₃ Subtype 5-HT Uptake 5-HT_(2A) Subtype5-HT_(1A) Subtype Compound ([3H]-BRL43694) ([3H]-paroxetin)([3H]-ketanserine) ([3H]-8OH-DPAT)  1 1.0 ± 0.2 632 ± 51  21110 ± 230030619 ± 6460   2 1.3 ± 0.2 503 ± 86  IN (10⁻⁶M) IN (10⁻⁶M)  3 2.6 ± 0.4175 ± 30  IN (10⁻⁶M) IN (10⁻⁶M)  4 0.7 ± 0.2 108 ± 15  IN (10⁻⁶M) IN(10⁻⁶M)  5  0.9 ± 0.06 485 ± 37  IN (10⁻⁶M) IN (10⁻⁶M)  6  0.7 ± 0.0895.8 ± 9.6  26477 ± 8700 IN (10⁻⁶M)  7  0.3 ± 0.09 — — —  8 1.8 ± 0.5 —— —  9 1.6 ± 0.6 123.7 ± 22   IN (10⁻⁶M) IN (10⁻⁶M) 10* 85.5 ± 16   — —— 11** 87 ± 37 — — — serotonin 118 ± 34  738 ± 117 — 7.3 1.3 quipazinc1.8 ± 0.3 31.3 ± 2.9  1808 ± 476 3649 ± 799  Granisetron  0.6 ± 0.06 — —— 6-NO₂-quipazine — 0.12 ± 0.01 — — 8-OH-DPAT — — — 1.18 ± 0.13

1. Compounds which can be represented by the general formula (I)indicated below:

and in which: X is CH or N; R is H, Cl or OR₁, in which R₁ is h or analkyl group having from 1 to 3 carbon atoms, Het is the 3-endotropylgroup (that is, the 8-methyl-8-azadicyclo[3.2.1]oct-3-yl group) or the3-quinuclidyl group [that is, the 1-azadicyclo[2.2.2]oct-3-yl group],and their salts produced from pharmaceutically acceptable inorganic ororganic acids:
 2. Compounds according to claim 1 in which X is CH. 3.Compounds according to claim 1 in which X is N.
 4. Compounds accordingto claim 2 in which Het is the 3-endotropyl group.
 5. Compoundsaccording to claim 2 in which Het is the 3-quinuclidyl group. 6.Compounds according to claim 3 in which Het is the 3-endotropyl group.7. Compounds according to claim 3 in which Het is the 3-quinuclidylgroup.
 8. A pharmaceutical preparation comprising, as an activesubstance, at least one of the compounds according to claim 1 or apharmaceutically acceptable salt thereof.
 9. A pharmaceuticalpreparation according to claim 8 for therapeutic use in accordance withits activity in the treatment of spontaneous or post-operative nauseaand vomiting or nausea or vomiting induced by cytostatic therapy.
 10. Apharmaceutical preparation according to claim 8 for the treatment ofpathological conditions of the SNC connected with imbalances in thephysiological neurone levels of serotonin, such as, for example,anxiety, panic attacks, psychosis, depression, Alzheimer's disease,etc., or with other causes correlated with the mechanism of action ofthe compounds according to claim
 1. 11. A pharmaceutical preparationaccording to claim 8 for use in the treatment of disorders of thegastrointestinal system such as non-ulcerous dyspepsia, oesophagitis dueto reflux, irritable colon and motility disturbances.
 12. Apharmaceutical preparation according to claim 8 for the symptomatictreatment of coughs.
 13. A pharmaceutical preparation according to claim8, further comprising pharmaceutically acceptable inactive ingredientsselected from the group which consists of vehicles, binders, flavorings,disaggregants, preservatives, humectants, and mixtures thereof, oringredients which facilitate transdermal absorption or which permitcontrolled release of the active substance over time.
 14. A method forthe preparation of a derivative of general formula (I) in which X and Rhave the meanings given in claim 1, and Het is the 3-endotropyl group,that is, the 8-methyl-8-azadicyclo[3.2.1]oct-3-yl group, comprising thesteps of: a) reacting esters of formula (IV)

in which X and R have the meanings given above and R′ may be methyl orethyl with N-bromosuccinimide in the presence of benzoyl peroxide in anorganic solvent such as, for example, carbon tetrachloride, at atemperature between ambient temperature and the reflux temperature ofthe solvent, for a period of between 1 and 8 h, to give thecorresponding 2-bromomethyl derivatives of formula III; b) reacting thebromo-derivatives of formula III

with a stoichiometric quantity of a heterocyclic amine of formula (III)NH₂-Het  (II) in which Het is the 3-endotropyl group, in the presence ofan inert tertiary base which functions as a proton acceptor, or with anexcess of the amine (II), at the reflux temperature of an anhydroussolvent, preferably toluene, for a period of between 1 and 24 h, to givethe corresponding amide derivatives of formula (I), which are isolatedas such or in the form of pharmaceutically acceptable salts, thecompounds of formula (I) in which R is OH being prepared by hot acidhydrolysis of the corresponding ethereal derivatives.
 15. A method forthe preparation of a derivative of general formula (I) in which X and Rhave the meanings given in claim 1 and Het is the 3-quinuclidyl group,that is, the 1-azadicyclo[2.2.2]oct-3-yl group, comprising the steps of:protecting the tertiary endocyclic nitrogen of the 3- aminoquinuclidineby alkylation with allyl bromide, reacting the non-isolated quaternizedintermediate (VI)

with the appropriate bromine derivative of formula (III) indicated inclaim 14, to give the quaternary ammoniacal salt of cyclized compound(V),

which, in turn, is non isolated, and deprotecting hot withn-dipropylamine in dimethyl formamide and in the presence of a catalyticquantity of Pd(PPh₃)₂Cl₂ to give the corresponding amide derivatives offormula (I), which are isolated as such or in the form ofpharmaceutically acceptable salts.